Moderator Neil Love MD A Oliver Sartor MD Victoria Sinibaldi MS CRNP William K Oh MD Doris Pindilli MS APNC AOCNP Faculty Challenging Cases in Prostate Cancer Oncologist and Nurse Investigators ID: 1035828
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1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.
2. ModeratorNeil Love, MDA Oliver Sartor, MDVictoria Sinibaldi, MS, CRNPWilliam K Oh, MDDoris Pindilli, MS, APN-C, AOCNPFaculty Challenging Cases in Prostate CancerOncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited FacultyThursday, April 25, 20136:30 AM – 8:00 AMWashington, DC
3. Challenging CasesOncologist and Nurse Investigators Consult on Actual Patients from the Practices of the Invited Faculty
4. Themes — Challenging Cases in OncologyA 10-hour Integrated CurriculumChallenges associated with the incorporation of new research findings and newly approved agents into practicePatient education on potential risks and benefits of specific oncologic treatmentsMonitoring and management of treatment side effects and toxicities
5. Themes — Challenging Cases in OncologyA 10-hour Integrated CurriculumParticipation in ongoing clinical trials as an important patient optionPsychosocial impact of cancer diagnosis and treatment — why all patients, even those with the same disease, are differentStrategies to cope with the stress of being an oncology professional
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10. AgendaModule 1: Sequencing systemic therapy for patients with castration-resistant prostate cancer (CRPC)48 yo man with metastatic PC (mPC) treated with docetaxel, sipuleucel-T and is currently receiving abiraterone — Ms Pindilli79 yo man who underwent radical prostatectomy 20 years ago with positive margins and develops bone metastases 16 years later — Ms Sinibaldi
11. AgendaModule 2: Novel bone-directed strategies – Radium-22365 yo man initially diagnosed with mPC and nodal involvement who received radium-223/docetaxel on a clinical trial — Ms SinibaldiModule 3: Role of chemotherapy in the management of mPC79 yo man diagnosed with mPC 12 years ago treated with abiraterone and is currently receiving enzalutamide — Ms Pindilli
12. New Agents/Regimens Recently Approved by the FDAwww.fda.govCancer Type AgentApproval DateColorectalBev on progression1/13Regorafenib9/12Aflibercept8/12ProstateEnzalutamide8/12Abiraterone 4/11Cabazitaxel6/10Sipuleucel-T4/10NHL: ALCLBrentuximab vedotin8/11NHL: T-cell lymphomaRomidepsin11/09Pralatrexate9/09Cancer Type AgentApproval DateLungNab paclitaxel10/12Crizotinib8/11BreastT-DM12/13Everolimus7/12Pertuzumab6/12Eribulin11/10MultiplemyelomaPomalidomide2/13Carfilzomib7/12
13. MODULE 1: SEQUENCING SYSTEMIC THERAPY FOR PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER (CRPC)
14. Case (from the practice of Ms Pindilli)48 yo computer engineer with mPC received docetaxel and then sipuleucel-T (sip-T)Develops rigors and pains with each dose of sip-TSignificant decline in PSA Currently receiving abirateroneExperienced problems with corticosteroids including weight gain and increased abdominal girth with moon faceDuring treatment, he went on a spiritual pilgrimage with his brother to IndiaLikes to see his scans and practices meditation, visualizing the disappearance of the tumors
15. Prostate Cancer ProgressionPrimary localized diseasePSA-only relapseMetastatic diseaseDeath
16. Mechanism of action and available clinical trial data for sipuleucel-T
17. Mechanism of Action for Sipuleucel-TSipuleucel-TSipuleucel-Twww.provengehcp.com
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19. Updated Results of the Phase III IMPACT Trial of Sipuleucel-T for mCRPCMedian time to objective progression: 14.6 versus 14.4 weeks Median overall survival: 25.8 versus 21.7 monthsKantoff P et al. ASCO GU Symposium 2010;Abstract 8; Kantoff P et al. N Engl J Med 2010;363(5):411-22.Sipuleucel-T(n = 341)2:1Placebo(n = 171)Eligibility (n = 512)Asymptomatic or minimally symptomatic mCRPCR
20. Possible Side Effects Associated with Sipuleucel-TChillsPyrexiaHeadachesInfluenza-like illnessKantoff P et al. ASCO GU Symposium 2010;Abstract 8.MyalgiaHypertensionHyperhidrosisGroin painSerious AEs ≥Grade 4 were well balanced between both arms
21. Response assessment in patients receiving immunotherapy
22. Case (from the practice of Ms Sinibaldi)79 yo man who underwent radical prostatectomy in 1993 at age 59, with positive marginsPSA rising, 3 years laterReceived salvage radiation therapyPSA risingReceived a series of endocrine therapies including intermittent androgen deprivation2009: Developed bone metastasesReceived additional lines of hormonal therapyPSA rising 4 months agoTreated with enzalutamide rather than abiraterone due to concerns about the requirement for corticosteroid administrationPSA declining; He is feeling relatively well
23. The Endocrine Axis in Prostate Cancer
24. The Endocrine Axis in Prostate Cancer
25. JPR7: Intermittent Androgen Suppression for Rising PSA After RadiotherapyContinuous androgen deprivation (CAD)RIntermittent androgen suppression (IAS)Pelvic RT completed >1 y priorPSA >3 ng/mL and > post-RT nadirCAD (n = 696)IAS (n = 690)Median OS9.1 y8.8 y7-y cumulative disease-related death rate15%18%Crook JM et al. N Engl J Med 2012;367(10):895-903.Patients with IAS experienced better global QoL, but benefit not universal
26. gCAD (n = 765)IAD (n = 770)Median OS5.8 y5.1 yNewly diagnosed mPCPSA >5 ng/mL Induction with goserelin + bicalutamide x 7 mosContinuous androgen deprivation (CAD)Intermittent androgen deprivation (IAD)R*SWOG-S9346 (INT-0162): Intermittent versus Continuous Androgen Deprivation in Hormone-Sensitive mPCHussain M et al. N Engl J Med 2013;368(14):1314-25.* If PSA <4 ng/mL on months 6 and 7
27. “…In addition to knowing little about which men in this population would benefit from treatment as compared with no treatment, we know little regarding the best possible timing of androgen-deprivation therapy for those clearly in need of treatment.Does early androgen-deprivation therapy in asymptomatic men with rising PSA levels provide more benefit than treatment in symptomatic men with metastases? This question bedevils our field, and we are no closer to an answer now than we were before.”Sartor O. N Engl J Med 2012;367(10):945-6.
28. Differential mechanisms of action and side-effect profiles of abiraterone and enzalutamide
29. Differential Mechanism of Action of Abiraterone versus EnzalutamideTestosteroneAndrogen Receptor EnzalutamideAbirateroneAcetateEnzalutamide+ AbirateroneAcetateTestosteroneTestosteroneAndrogen Receptor Androgen Receptor
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31. Phase III COU-AA-301 StudyFizazi K et al. Lancet Oncol 2012;13(10):983-92.Median overall survival: 15.8 versus 11.2 monthsAbiraterone + Prednisone (n = 797)R2:1Placebo + Prednisone (n = 398)Eligibility (n = 1,195)Histologically/cytologically confirmed mCRPCFailure of docetaxel≤2 prior chemotherapiesPSA progression
32. FDA Approves the Expanded Use of Abiraterone Acetate in Combination with Prednisone for mCRPC“On December 10, 2012, the Food and Drug Administration (FDA) approved an expanded indication for abiraterone acetate in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer before chemotherapy.”The approval was based on the Phase III COU-AA-302 trial.http://www.cancer.gov/cancertopics/druginfo/fda-abirateroneacetate
33. Possible Side Effects Associated with AbirateroneAll GradeArthralgiaUrinary tract infectionFluid retention or edemaHypokalemiaCardiac disordersAtrial fibrillationLFT abnormalitiesHypertensionGrade 3/4 Adverse EventsFatigueAnemiaBack painBone painFizazi K et al. Lancet Oncol 2012;13(10):983-92; Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518.
34. FDA Approves Enzalutamide for mCRPC“On August 31, 2012, the Food and Drug Administration (FDA) approved enzalutamide for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.”The approval was based on the Phase III AFFIRM trialhttp://www.cancer.gov/cancertopics/druginfo/fda-enzalutamide
35. Primary, secondary, and quality-of-life endpoint results from the Phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitorDe Bono JS et al. Proc ASCO 2012;Abstract 4519
36. Phase III AFFIRM StudyDe Bono JS et al. Proc ASCO 2012;Abstract 4519.Enzalutamide (160 mg/d)(n = 800)R2:1Placebo (n = 399)Eligibility (n = 1,199)Patients with mCRPCFailure of docetaxel-based chemotherapy
37. Phase III AFFIRM Study Results in Favor of EnzalutamideMedian overall survival: 18.4 versus 13.6 monthsPSA progression-free survival: 8.3 versus 3.0 monthsTime to first skeletal-related event: 16.7 versus 13.3 monthsObjective response rate: 28.9% versus 3.8%QoL response (10-point increase in overall score): 43.2% versus 18.3%De Bono JS et al. Proc ASCO 2012;Abstract 4519.
38. Possible Side Effects Associated with EnzalutamideFatigueCardiac disordersMyocardial infarctionLiver function abnormalitiesSeizuresDe Bono JS et al. Proc ASCO 2012;Abstract 4519.
39. gPossible Side Effects Associated with Enzalutamide: SeizuresDe Bono JS et al. Proc ASCO 2012;Abstract 4519.Scher HI for the AFFIRM Investigators. N Engl J Med 2012;367(13):1187-97.CASE12345Time on study2 months10 months2 months5 months10 monthsOn study drug?YesYesYesOff trial drug for 26 daysYesSeizure typeFocal onsetGeneralizedComplex partial statusFocal onsetUnknown, fall not witnessedRecurrenceNoNoNoNoNoPotential confounding factorsLarge 5 x 4-cm temporal lobe brain metastasesIV lidocaine inadvertently administered just before seizureAtrophy and leukoaraiosis on brain MRI; nil elseMultiple CNS metastases: Eye, meninges, cerebellarAlcohol excess; started on haloperidol 7 days prior
40. Ongoing Phase III PREVAIL Studywww.clinicaltrials.gov; April 2013 (NCT01212991)Primary endpoints: Overall survival, progression-free survivalEnzalutamideR2:1Placebo Target accrual (n = 1,680)Histologically confirmed PCOngoing ADTNo prior chemotherapyAsymptomatic/mildly symptomatic
41. Sequential use of secondary hormonal agents and ongoing investigations of combination strategies
42. www.clinicaltrials.gov; April 2013 (NCT01650194)Enzalutamide+AbirateroneOngoing Phase II Trial of Enzalutamide in Combination with AbirateronePrimary endpoints:Nature, frequency and severity of adverse eventsSafetyTarget accrual (n = 60)Histologically/cytologically confirmed CRPCBone metastasesOngoing androgen deprivation therapy
43. MODULE 2: NOVEL BONE-DIRECTED STRATEGIES — RADIUM-223
44. Case (from the practice of Ms Sinibaldi)65 yo man initially diagnosed with mPC and nodal involvement in 2006Responded to an LHRH agonist2009: Widespread bone metastasesReceived multiple therapies including ketoconazole, sipuleucel-T, abiraterone and radium-223/docetaxel on a clinical trialExperienced pain relief but also myelosuppressionCurrently receiving enzalutamide
45. Mechanism of action and administration of radium-223
46. CalciumStrontiumRadiumRadium Acts as a Calcium MimeticMcDevitt MR et al. Eur J Nucl Med 1998;25(9):1341-51.Barium
47. Mechanism of Action of and Administration of Radium-223Radium-223 is a short-range but high-energy alpha-emitting particleIt targets osteoblastic bone metastases by acting as a calcium mimeticPerez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007. 2-10 cell diameter range of alpha-particleRadium-223
48. Available clinical trial data and ongoing trials with radium-223
49. Phase III ALSYMPCA TrialParker C et al. Proc ESMO 2012;Abstract 898PD. Median overall survival: 14.9 versus 11.3 monthsTime to first skeletal-related event: 15.6 versus 9.8 monthsBone pain Grade >3: 18% versus 23%Radium-223+ Best supportive care(n = 614)R2:1Placebo +Best supportive care(n = 307)Eligibility (n = 921)Confirmed symptomatic CRPC≥2 bone metastasesNo visceral metastasesPost docetaxel/unfit for docetaxel
50. Possible Side Effects Associated with Radium-223Bone painDiarrheaNauseaVomitingConstipationAnemiaNeutropeniaThrombocytopeniaParker C et al. Proc ESMO 2012;Abstract 898PD.
51. Side effects and toxicities of radium-223 versus existing radiopharmaceuticals
52. Side-Effect Profile of Radium-223 versus Other RadiopharmaceuticalsRadiopharmaceuticalSide effects Radium-223 (clinical)Minor GI toxicities; mild neutropenia/thrombocytopenia1Strontium-89 (clinical)Increased but tolerable hematologic toxicity2Samarium-153 (clinical)Significant leukopenia and thrombocytopenia31 Harrison MR et al. Cancer Manag Res 2013;5:1-14; 2 Porter AT et al. Int J Radiat Biol Phys 1993;25(5):805-13; 3 Harrison MR et al. Cancer Manag Res 2013;5:1-14.
53. Potential use of radium-223 with other systemic therapies (eg, hormonal therapy, chemotherapy, other bone-directed agents)
54. www.clinicaltrials.gov; April 2013 (NCT01106352)Radium-223 + DocetaxelRDocetaxel onlyPotential Use of Radium-223 with Other Systemic Therapies (A Phase I/II Trial)Primary endpoint:Assessment of dose-limiting toxicitiesSafetyTarget accrual (n = 60)Histologically/cytologically confirmed mCRPC≥2 bone metastasesEligible for docetaxel
55. MODULE 3: ROLE OF CHEMOTHERAPY IN THE MANAGEMENT OF mPC
56. Case (from the practice of Ms Pindilli)79 yo man diagnosed 12 years ago with mPCReceived multiple systemic treatments including abiraterone on a clinical trialReceived several alternative therapiesCurrently receiving enzalutamide2005: Together with his wife, adopted a 3-month old daughter Spending time with his family is his greatest concern
57. Berthold DR et al. J Clin Oncol 2008;26(2):242-245; Tannock IF et al. N Engl J Med 2004;351:1502-12.Median overall survival: 19.2 versus 17.8 versus 16.3 months50% decrease in serum PSA: 45% versus 48% vs 32%Pain reduction: 35% versus 31% versus 22%Improved QoL: 22% versus 23% versus 13%Docetaxel q 3 wk + PrednisoneR1:1Mitoxantrone + PrednisonePhase III TAX-327 Study of DocetaxelDocetaxel q wk + PrednisoneN = 1,006Patients with mCRPCIncreasing PSA
58. www.clinicaltrials.gov; April 2013 (NCT00417079)De Bono JS et al. Lancet 2010;376(9747):1147-1154. Median overall survival: 15.1 versus 12.7 monthsMedian progression-free survival: 2.8 vs 1.4 monthsMost common AE > Grade 3 with cabazitaxel: neutropenia, diarrheaCabazitaxel + Prednisone(n = 378)R1:1Mitoxantrone + Prednisone(n = 377) Phase III TROPIC Study of CabazitaxelEligibility (n = 755)Patients with progressive mCRPC during or after treatment with a docetaxel-based regimen
59. De Bono JS et al. Lancet 2010;376(9747):1147-1154. Possible Side Effects Associated with Docetaxel and CabazitaxelNeutropeniaLeukopeniaAnemiaDiarrheaFebrile neutropeniaFatigueAstheniaBack painNauseaVomitingHematuriaAbdominal painPeripheral neuropathy